4ys7

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'''Unreleased structure'''
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==Co-crystal structure of 2-[2-(5,8-dimethyl[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl]-3-methyl-3H-imidazo[4,5-f]quinoline (compound 39) with PDE10A==
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<StructureSection load='4ys7' size='340' side='right' caption='[[4ys7]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4ys7]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YS7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YS7 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4GK:2-[2-(5,8-DIMETHYL[1,2,4]TRIAZOLO[1,5-A]PYRAZIN-2-YL)ETHYL]-3-METHYL-3H-IMIDAZO[4,5-F]QUINOLINE'>4GK</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4yqh|4yqh]]</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ys7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ys7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ys7 RCSB], [http://www.ebi.ac.uk/pdbsum/4ys7 PDBsum]</span></td></tr>
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</table>
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== Function ==
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[[http://www.uniprot.org/uniprot/PDE10_HUMAN PDE10_HUMAN]] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.<ref>PMID:17389385</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The design and synthesis of highly potent, selective orally bioavailable inhibitors of PDE10A is reported. Starting with an active compound of modest potency from a small focused screen, we were able to evolve this series to a lead molecule with high potency and selectivity versus other PDEs using structure-based design. A systematic refinement of ADME properties during lead optimization led to a lead compound with good half-life that was brain penetrant. Compound 39 was highly potent versus PDE10A (IC50=1.0nM), demonstrated high selectivity (&gt;1000-fold) against other PDEs and was efficacious when dosed orally in a rat model of psychosis, PCP-induced hyperlocomotion with an EC50 of 1mg/kg.
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The entry 4ys7 is ON HOLD
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Evolution and synthesis of novel orally bioavailable inhibitors of PDE10A.,Burdi DF, Campbell JE, Wang J, Zhao S, Zhong H, Wei J, Campbell U, Shao L, Herman L, Koch P, Jones PG, Hewitt MC Bioorg Med Chem Lett. 2015 May 1;25(9):1864-8. doi: 10.1016/j.bmcl.2015.03.050., Epub 2015 Mar 26. PMID:25863433<ref>PMID:25863433</ref>
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Authors: Burdi, D.F., Herman, L., Wang, T.
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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Description:
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== References ==
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[[Category: Unreleased Structures]]
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<references/>
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[[Category: Burdi, D.F]]
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__TOC__
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</StructureSection>
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[[Category: Burdi, D F]]
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[[Category: Herman, L]]
[[Category: Wang, T]]
[[Category: Wang, T]]
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[[Category: Herman, L]]
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[[Category: Co-crystal]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Inhibitor]]
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[[Category: Pde10a]]

Revision as of 11:38, 30 April 2015

Co-crystal structure of 2-[2-(5,8-dimethyl[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl]-3-methyl-3H-imidazo[4,5-f]quinoline (compound 39) with PDE10A

4ys7, resolution 2.50Å

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